U.S. patent number 8,075,840 [Application Number 12/200,459] was granted by the patent office on 2011-12-13 for automatic multi-purpose analyzer.
This patent grant is currently assigned to Hitachi High-Technologies Corporation. Invention is credited to Takanori Shimane, Katsuaki Takahashi.
United States Patent |
8,075,840 |
Shimane , et al. |
December 13, 2011 |
Automatic multi-purpose analyzer
Abstract
An automatic multi-purpose analyzer performs qualitative and
quantitative analysis of biological samples such as blood, urine,
etc. and includes a plurality of analysis units connected in series
through a transfer line for transferring the sample, wherein
failure caused by incorrect surface detection is resolved. The
plurality of analysis units are connected in series through a
transfer line for transferring a sample, each analysis unit
including a pipetting mechanism for pipetting the sample, and
wherein each of the analysis units includes a transmission
mechanism for transmitting information about the amount of sample,
obtained upon sample pipetting by the pipetting mechanism of each
analysis unit, to other analysis units.
Inventors: |
Shimane; Takanori (Hitachinaka,
JP), Takahashi; Katsuaki (Hitachinaka,
JP) |
Assignee: |
Hitachi High-Technologies
Corporation (Tokyo, JP)
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Family
ID: |
39894312 |
Appl.
No.: |
12/200,459 |
Filed: |
August 28, 2008 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20090060785 A1 |
Mar 5, 2009 |
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Foreign Application Priority Data
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Aug 31, 2007 [JP] |
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2007-224998 |
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Current U.S.
Class: |
422/63; 442/64;
442/65; 422/501; 422/500; 442/67; 442/66; 73/1.74 |
Current CPC
Class: |
G01N
35/1011 (20130101); G01F 23/265 (20130101); Y10T
442/2057 (20150401); G01N 2035/1025 (20130101); Y10T
442/2041 (20150401); Y10T 442/2066 (20150401); Y10T
442/2049 (20150401) |
Current International
Class: |
G01N
21/00 (20060101) |
Field of
Search: |
;422/63-67,99-100,500-501 ;73/304,1.74 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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1 562 027 |
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Aug 2005 |
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EP |
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3-189586 |
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Aug 1991 |
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JP |
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2988362 |
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Oct 1999 |
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JP |
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2988362 |
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Oct 1999 |
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JP |
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2006-010363 |
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Jan 2006 |
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JP |
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Primary Examiner: Nagpaul; Jyoti
Attorney, Agent or Firm: Mattingly & Malur, P.C.
Claims
What is claimed is:
1. An automatic multi-purpose analyzer having a plurality of
analysis units connected in series through a transfer line for
transferring a sample liquid, each of the analysis units including
a pipetting mechanism for pipetting sample liquid and for providing
a liquid surface level detecting mechanism, wherein: each of the
analysis units includes a transmission mechanism configured to
transmit information about a height of a liquid surface level of a
sample vessel obtained by the liquid surface level detecting
mechanism to other analysis units, the information being obtained
upon sample pipetting by the pipetting mechanism of each of the
analysis units; a liquid surface level detecting mechanism provided
in a pipetting mechanism of another analyzer for which the
information about the height of the liquid surface level is
transmitted by the transmission mechanism is controlled, wherein:
the liquid surface level detecting mechanism which transmits the
information is an electric liquid surface level detecting
mechanism, and the liquid surface level detecting mechanism to
which the information is transmitted and controls the liquid
surface level detecting mechanism is a capacitive liquid surface
level detecting mechanism; and the liquid surface level detecting
mechanism, to which the information is transmitted and controls the
liquid surface level detecting mechanism, is configured to
recognize a zero level which is a higher predetermined level than
the height of the liquid surface level obtained by the liquid
surface level detecting mechanism which transmits the information,
and is configured to detect the liquid surface level based on a
capacitance at the zero level.
2. An automatic multi-purpose analyzer having a plurality of
analysis units connected in series through a transfer line for
transferring sample liquid, each of the analysis units including a
pipetting mechanism for pipetting sample liquid and for providing a
liquid surface level detecting mechanism, wherein: each of the
analysis units includes a transmission mechanism configured to
transmit information about a height of a liquid surface level of a
sample vessel obtained by the liquid surface level detecting
mechanism to other analysis units, the information being obtained
upon sample pipetting by the pipetting mechanism of each of the
analysis units; and a control unit configured to verify whether
information of the height of the liquid surface level obtained by
the liquid surface level detecting mechanism provided in the
pipetting mechanism of another analyzer is correct.
Description
INCORPORATED BY REFERENCE
The present application claims priority from Japanese application
2007-224998 filed on Aug. 31, 2007, the contents of which are
hereby incorporated by reference into this application.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to an automatic multi-purpose
analyzer which performs qualitative and quantitative analysis of
biological samples such as blood, urine, etc. More particularly,
the present invention relates to an automatic multi-purpose
analyzer having a function for transferring a sample between a
plurality of analysis units through a transfer apparatus.
2. Description of the Related Art
With the excellent measurement reproducibility, quantitative
characteristics, and rapid analysis capabilities, a remarkably
increasing number of automatic analyzers are used mainly in
inspection centers and large hospitals. In particular, inspection
centers which collect samples from local minor hospitals and
analyze the samples on behalf of these hospitals are demanding a
high-throughput analyzer capable of analyzing a number of samples
in a short time. In order to meet this demand, a modularized
analyzer having a plurality of analysis units connected in series
through a transfer line is commercially available. Such a
modularized analyzer is described, for example, in Japanese Patent
No. 2988362.
SUMMARY OF THE INVENTION
An object of the present invention is to provide an automatic
modularized multi-purpose analyzer that attains higher
throughput.
In order to attain the above-mentioned object, the present
invention is configured as follows:
An automatic multi-purpose analyzer having a plurality of analysis
units connected in series through a transfer line for transferring
sample liquid, each of the analysis units including a pipetting
mechanism for pipetting sample liquid, wherein each of the analysis
units includes a transmission mechanism for transmitting
information about the amount of a sample liquid to other analysis
units, the information being obtained upon sample pipetting by the
pipetting mechanism of each of the analysis units
An example will be explained below.
A mechanism used for first detecting the liquid surface to
recognize its height (hereinafter referred to as surface height or
surface level interchangeably) securely measures the surface
height. Such a mechanism is based on a reliable liquid surface
method. Information on the surface height is transferred to another
analysis unit in which a capacitive sample probe is inserted into
and then lowered inside a vessel. With the capacitive probe,
capacitance fluctuation from a certain timing is monitored and,
when the liquid surface is judged, lowering operation of the probe
is stopped. This timing is referred to as reset time. With a
conventional analyzer, it is not possible to know the height of the
vessel at which the liquid surface resides and therefore monitoring
is constantly required while the probe is lowered toward the
vessel.
Therefore, when the tip of the sample probe almost reaches the
entrance of the vessel, a reset signal is generated and a zero
point of capacitance is set there. The capacitance gradually
increases as the probe is inserted into and then lowered inside a
deep sample vessel. When the probe comes in contact with the liquid
surface, a hump signal fluctuation is obtained. When the analyzer
captures the hump signal fluctuation, it recognizes the liquid
surface. However, such a hump signal fluctuation also occurs owing
to discharge noise or vibration generated while the probe is
lowered and thereby incorrect surface detection will be made. With
the present invention, the information on the place where the
surface height is present can be obtained before the probe is
lowered and therefore the reset signal is generated after the probe
has approached the vicinity of the liquid surface (3 millimeters
above the liquid surface). This makes it possible to ignore a hump
signal occurring owing to discharge noise or vibration generated
during lowering operation.
The liquid surface can be correctly detected if discharge noise
during lowering operation can be ignored.
Fortunately, with a large-sized modularized automatic analyzer, a
unit for measuring electrolyte in a sample is disposed, in many
cases, on an upstream side of the transfer line for transferring
the sample (because electrolyte measurement has urgency, that is,
measurements should be obtained as soon as possible). Since a
reaction vessel (dilution mixture vessel) into which the sample is
discharged is a large-sized type, an electrolyte sample probe may
be an electric probe, which can be easily inserted into the vessel.
Therefore, it is the sample probe of an electrolyte analysis unit
that is first inserted into the sample vessel. This sample probe
correctly measures the surface height and transfers information on
the height to another analysis unit for colorimetric
measurement.
Sharing between analysis units information about the sample and
liquid surface in the sample vessel obtained in the inspection
operation makes it possible to omit surface detection to be
performed by subsequent analysis units, thus improving the analysis
efficiency. Further, even when liquid surface detection
(hereinafter referred to simply as surface detection) is not
omitted, if surface height information obtained by an analysis unit
differs from surface height information obtained by the subsequent
analysis unit, it can be determined that incorrect surface
detection has been made because of, for example, air bubbles
produced on the liquid surface of the sample. Thus, more reliable
analysis can be attained.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic diagram showing the overall configuration of
an analysis unit according to the present invention.
FIG. 2 is a schematic diagram showing the overall configuration of
an automatic multi-purpose analyzer having a plurality of analysis
units.
FIG. 3 shows a problem to be solved by the present invention.
FIG. 4 is a schematic diagram of the automatic multi-purpose
analyzer according to the present invention.
FIG. 5A is a graph showing a relation between the probe lowering
speed and time, and FIG. 5B showing a relation between a surface
detection signal output and time.
FIG. 6 is a schematic diagram of an electric surface detection
apparatus.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
An automatic multi-purpose analyzer pipettes sample liquid such as
blood, urine, etc. and reagent liquid into a reaction vessel and
analyzes the mixture thereof. In recent years, a capacitive liquid
level detection method has been used widely for liquid level
detection because the outer diameter of its sample probe can be
reduced. The reason the outer diameter reduction is necessary is
that a reaction vessel has been remarkably reduced in size to about
2 mm.times.4 mm because of reduced amounts of reaction liquid.
Accordingly, a capacitive probe having an outer diameter of 1
millimeter or less is suitable for use as a sample probe that is
inserted into such a small reaction vessel. Although an electric
probe is most reliable because it is free from misdetection, this
type of probe requires two electrodes, which increases the outer
diameter to 4 millimeters; thus, the probe may not fit into a
reaction vessel. Thus, the capacitive liquid level detection method
has been used widely. With the capacitive liquid level detection
method, discharge noises may occur depending on the charged state
in the sample vessel, resulting in liquid level misdetection by a
sample pipetting mechanism.
A present modularized automatic multi-purpose analyzer commonly
includes detection means for detecting a liquid surface level for
each pipetting mechanism. In a sample pipetting mechanism of a
modular analysis unit, even if a liquid surface level is
misdetected due to discharge noises, that modular analysis unit
alone cannot determine whether or not misdetection has occurred. In
the automatic multi-purpose analyzer having multiple modular
analysis units according to the present invention, a modular
analysis unit shares with other modular analysis units liquid
surface level information (amount of sample liquid) obtained by the
analysis unit, which allows any of the analysis units to verify
liquid surface level information obtained from the pipetting
devises of other analysis units. This allows the automatic
multi-purpose analyzer to avoid incorrect analysis caused by
incorrect liquid surface level information.
An embodiment of the present invention will be described below with
reference to the accompanying drawings.
FIG. 1 is a schematic diagram of the periphery of pipetting
mechanisms of a common automatic analyzer. Since the functions of
respective sections are well-known, detailed description of the
functions will be omitted. The automatic multi-purpose analyzer is
configured such that a sample pipetting arm 2 of a sample pipetting
mechanism 1 moves vertically and rotates, and a sample pipetting
probe 105 attached to the sample pipetting arm 2 suctions a sample
liquid 7 in a sample vessel 101 installed on a
horizontally-rotating sample disk 102 and discharges the sample
liquid 7 into a reaction vessel 106. As shown in FIG. 1, the sample
disk 102 is typically universally designed to accommodate sample
vessels; that is, a sample vessel 101 can be placed directly on the
sample disk 102, or the sample vessel 101 can be placed on a test
tube (not shown) installed on the sample disk 102.
The configuration of the automatic multi-purpose analyzer of FIG. 1
will be explained below in more detail. A rotatable reagent disk
125 installs thereon reagent bottles 112, each being associated
with a plurality of analysis items subjected to analysis. A reagent
pipetting probe 110 attached to a movable arm pipettes a
predetermined amount of reagent liquid from a reagent bottle 112 to
a reaction vessel 106.
The sample pipetting probe 105 performs sample suction and
discharge operations in response to the operation of a sample
syringe pump 107. The reagent pipetting probe 110 performs reagent
suction and discharge operations in response to the operation of a
reagent syringe pump 111. Analysis items to be analyzed for each
sample are input from input devices such as a keyboard 121 or the
screen of a CRT 118. The operation of each unit in the automatic
multi-purpose analyzer is controlled by a computer 103.
With the intermittent rotation of the sample disk 102, a sample
vessel 101 is transferred to a sample suction position, and the
sample pipetting probe 105 is lowered into the sample vessel 101 in
a halted state. When the tip of the sample pipetting probe 105
comes in contact with the surface of the sample liquid with the
lowering operation of the sample pipetting probe 105, a liquid
surface level detector 151 outputs a detection signal, and the
computer 103 performs control so as to stop the lowering operation
by the drive unit of the movable sample pipetting arm 2 based on
the detection signal. Then, the sample pipetting probe 105 suctions
a predetermined amount of the sample liquid and rises to the upper
dead center. While the sample pipetting probe 105 is suctioning a
predetermined amount of the sample liquid, a pressure detection
circuit 153 monitors pressure fluctuation inside a passage between
the sample pipetting probe 105 and the sample syringe pump 107 by
use of a signal from a pressure sensor 152. If an abnormal pressure
fluctuation is detected during the suction operation, that means
the predetermined amount of the sample liquid may not have been
suctioned, and an alarm is therefore added to related analysis
data.
Then, the sample pipetting arm 2 horizontally swings to lower the
sample pipetting probe 105 at the position of a reaction vessel 106
on a reaction disk 109, and the sample pipetting probe 105
discharges the sample liquid into the reaction vessel 106. When the
reaction vessel 106 containing the sample is moved to a reagent
addition position, a reagent liquid associated with a relevant
analysis item is added from the reagent pipetting probe 110 into
the reaction vessel 106. During the sample and reagent pipetting
operations, the liquid surface levels of the sample liquid in the
sample vessel 101 and of the reagent liquid in the reagent bottle
112 are detected. The mixture of the sample and reagent in the
reaction vessel is stirred by a stirring device 113. The reaction
vessel containing the mixture is then transferred to measurement
means. At the same time, an actuator opens shielding means of a
light source 114, and the luminescence value or absorbance of the
mixture is measured by a photo-multiplier 115 or photometer as the
measurement means. The resultant luminescence signal passes through
an A/D converter 116 and then is supplied to the computer 103
through an interface 104 to calculate concentrations for analysis
items. Analysis results are printed out by a printer 117 through
the interface 104 or displayed on the screen of the CRT 118 and, at
the same time, stored in a hard disk 122 or memory. The reaction
vessel 106 that completed the photometry is cleaned at the position
of a cleaning mechanism 119. A cleaning pump 120 supplies cleaning
water to the reaction vessel while discharging waster water from
the reaction vessel. In the example of FIG. 1, three concentric
rows of vessel holding sections are formed on the sample disk 102
so as to concentrically set sample vessels 101 in three rows, and a
sample suction position for the sample pipetting probe 105 is
provided in each concentric row.
An example of an automatic multi-purpose analyzer configured with a
plurality of analysis units connected in series will be explained
below with reference to FIG. 2. The plurality of analysis units
having the above-mentioned functions are connected in series by a
sample transfer unit. An analyzer control unit serves as a user
interface of the automatic multi-purpose analyzer, and interfaces
inside the automatic multi-purpose analyzer are connected via
suitable communication means such as Ethernet (registered
trademark). A sample vessel is loaded from the sample loading unit
and then transferred by the sample transfer unit to an analysis
unit which is requested for analysis. The sample vessel that
completed analysis is suitably transferred to the sample unloading
unit. FIG. 2 shows a specific example of two different sample
transfer paths: one is for a case where only an analysis unit 1
(10) is requested for analysis, and the other for a case where the
analysis unit 1 (10), an analysis unit 2 (11), and an analysis unit
4 (13) are requested for analysis.
Problems with present automatic multi-purpose analyzers will be
explained below with reference to FIG. 3. Assume that the sample
transfer unit is requested to transfer a sample vessel 101 to the
analysis unit 1 (10), the analysis unit 2 (11), and the analysis
unit 4 (13) for analysis, as stated above for FIG. 2. The sample
vessel 101, requested by the analyzer control unit 16, is loaded
from the sample loading unit 14 and then supplied to the analysis
unit 1 (10) for analysis. As mentioned above, the sample pipetting
probe 105 is lowered into the sample vessel 101, the lowering
operation by the drive unit of the movable arm (sampling arm) 2 is
stopped, and the pipetting probe 105 suctions a predetermined
amount of sample. If the pipetting probe detects the liquid surface
of the sample during the suction operation, the sample is
transferred from the analysis unit 1 (10) to the analysis unit 2
(11) and then to the analysis unit 3 (12) so as to be subjected to
pipetting operation by each individual analysis unit. Accordingly,
even if the sample is normally detected by the analysis unit 1
(10), the sample is subjected to incorrect detection by the
pipetting probe of the analysis unit 2 and then transferred to the
sample unloading unit 15, resulting in degraded reliability of
overall automatic analysis.
The operation of the automatic multi-purpose analyzer according to
the present invention will be explained below with reference to
FIGS. 3 and 4.
The analysis unit 1 (10) includes an electrolyte (Na+, K+, and
Cl-ion) measurement apparatus. Since the sample probe 20 of the
analysis unit 1 (10) is an electric probe 21, the sample probe 20
is highly reliable and therefore almost never fail. Further, a
detection signal obtained is clear because of the ON/OFF
(conducting/nonconducting) detection method.
A liquid surface level 22 can also be correctly recognized. Even if
there is not a request on electrolyte, the probe is inserted to
measure the liquid surface level 22 and then lowered to a suction
position 23. The liquid surface level information is once
transferred to the CPU of the apparatus control unit 16 controlling
the entire automatic multi-purpose analyzer and then to the
analysis unit 2 (11) therefrom. A pipetting probe 24 of the
analysis unit 2 (11) is a capacitive probe having a small outer
diameter, and therefore can be easily inserted into a reaction
vessel.
The liquid surface level information is transferred to the
pipetting probe 24 of the analysis unit 2 (11). Based on the
information, the pipetting probe 24 is lowered at high speed until
it reaches a position 25, 5 millimeters above a surface position 22
of the analysis unit 1 during sample suction operation. Then, the
lowering speed of the pipetting probe 24 is slowed down until it
reaches a position 26, 2 millimeters above the surface position 22.
The lowering operation is continued at a constant low speed and
then a liquid surface 27 is detected. The pipetting probe 24 is
stopped at a position 28, 1.5 millimeters below the liquid surface.
FIG. 5(1) is a graph showing a relation between the probe lowering
speed and time, and FIG. 5(2) showing a relation between a surface
detection signal output and time. With a conventional automatic
multi-purpose analyzer, immediately before lowering operation
starts (45), a reset signal is generated when the tip of the probe
is in the vicinity of the entrance of the sample vessel, and the
output voltage at this timing is set as a zero point. In FIG. 5(1),
a detection speed curve 41 of the conventional automatic
multi-purpose analyzer indicates that the probe moves at a constant
speed until it reaches the liquid surface while a speed curve 40 of
the automatic multi-purpose analyzer according to the present
invention indicates that the probe moves at high speed. With a
detection signal pulse curve of FIG. 5(2), the probe is lowered
into the sample vessel while observing a detection signal. When the
detection signal reaches and exceeds a fixed value (threshold value
51), it is judged that the probe has come in contact with the
liquid surface. However, depending on the charging state in the
sample vessel (in particular, a plastic blood collection pipe is
easy to be charged and, after a centrifuge or the like is used for
serum separation, the blood collection pipe is charged very
intensively), the capacitance of a charge-time pulse signal 49
gradually increases as the probe is lowered, and exceeds the
threshold value 51 although the probe has not yet come in contact
with the liquid surface. In this case, a portion B (44) is
incorrectly detected. If discharge takes place between the sample
vessel inner surface and the probe, a hump waveform is generated in
a pulse signal 48 at a portion A (43) during probe lowering
operation. Also if the hump signal exceeds the threshold value 51,
incorrect surface detection results. Since a pulse signal 50
according to the present invention transmits the liquid surface
level with a certain accuracy, a reset trigger signal of the
surface detection signal is generated 2 millimeters above the
liquid surface (42). With the charge-time pulse signal 49, an arrow
portion 46 is reacknowledged as a zero point; with the
discharge-time pulse signal 48, an arrow portion 47 is
reacknowledged as a zero point.
The probe 52 is vertically moved by a stepping motor. Therefore, it
is necessary to lower the probe 52 while counting the number of
pulses given to the motor and, when the number of pulses reaches a
certain number, generate a reset trigger signal, and lowers the
probe 52 into a sample vessel 53.
Since capacitance fluctuations from the reacknowledged zero points
are monitored, the signal increases only slightly by charge, and
discharge does not take place, during a short time (and in a short
distance) since the probe is 2 millimeters above the liquid surface
until it comes in contact with the liquid surface, remarkably
increasing the reliability of surface detection.
Using the zero point as a reference position of the pipetting start
position of the analysis unit 2 (11), the probe detects the liquid
surface 27 from the reference position, and surface information
having correction for lowered liquid surface by sample suction 29
is transmitted to an analysis unit 4 (13). The analysis unit 4 (13)
performs the same pipetting probe control as that performed by
other analysis units. This makes it possible to reduce incorrect
surface detection operations by the pipetting probe of each
analysis unit to shorten the processing time, thus contributing to
provision of an optimal operating environment for the automatic
multi-purpose analyzer.
Although the first analysis unit installs therein an electrolyte
measurement unit, it is also possible to dispose a mechanism
dedicated for surface detection for securely measuring the liquid
surface level between the sample loading unit 14 and the first
analysis unit, and transmit the surface information to each
analysis unit.
A configuration for surface detection as shown in FIG. 6 is also
possible. In the first analysis unit, an arm 30 is provided with
two sample probes 31 in parallel with each other, and conduction
between the two probes is monitored. Recently, reaction vessels 32
are placed at very small intervals, that is, about 3 millimeters;
however, it is easy to insert the probes into a sample vessel 33
(having an inner diameter of 8 millimeters) with the original gap
between nozzles.
As means for first inserting the probe into the vessel to measure
the liquid surface, it is also possible to lower the probe while
discharging air from the tip of the nozzle and detect pressure
fluctuation inside the nozzle at the moment when the probe comes in
contact with the liquid surface.
There is another advantage if the liquid surface is preliminarily
known. If the liquid surface is approximately known, the sample
probe can be lowered at high speed and slowed down in the vicinity
of the liquid surface and accordingly the pipetting time can be
shortened, thus improving the analysis throughput of the automatic
multi-purpose analyzer.
* * * * *